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Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

Previous MRI studies consistently reported iron accumulation within the striatum of patients with Huntington’s disease (HD). However, the pattern and origin of iron accumulation is poorly understood. This study aimed to characterize the histopathological correlates of iron-sensitive ex vivo MRI contrast change in HD brains. To this end, T2*-weighted 7T MRI was performed on postmortem tissue of the striatum of three control subjects and 10 HD patients followed by histological examination. In addition, formalin-fixed paraffin-embedded material of three control subjects and 14 HD patients was selected for only histology to identify the cellular localization of iron using stainings for iron, myelin, microglia and astrocytes. As expected HD striata showed prominent atrophy. Compared to controls, the striatum of HD patients was in general more hypointense on T2*-weighted high-field MRI and showed a more intense histopathological staining for iron. In addition, T2*-weighted MRI identified large focal hypointensities within the striatum of HD patients. Upon histological examination, these large focal hypointensities frequently colocalized with enlarged perivascular spaces and iron was found within the vessel wall and reactive astrocytes. In conclusion, we show that the striatum of HD patients has a distinctive phenotype on T2*-weighted MRI compared to control subjects. On ex vivo MRI, these contrast changes are heavily biased by enlarged perivascular spaces from which it is currently unknown whether this is a fixation artefact or a disease specific observation. Clinically, the observation of iron within reactive astrocytes is of importance for the interpretation and understanding of the potential underlying mechanisms of T2*-weighted MRI results in HD patients.

Background: Huntington's Disease (HD) is an incurable disease of the adult brain. Massive changes in gene expression are a prominent feature. Epigenetic effects have been reported to be implicated in HD, but the role of chromatin is not well understood. We tested if the chromatin state of dysregulated genes in HD is affected at a genome-wide scale and examined how epigenetic processes are associated with CpG-island-mediated gene expression. Methods: Our general approach incorporates computational and functional analysis of public data before embarking on expensive wet-lab experiments. We compared the location in the genome of the genes that were deregulated in HD human brain, obtained from public gene expression data, to the location of particular chromatin marks in reference tissues using data from the ENCODE project. Results: We found that differentially expressed genes were enriched in the active chromatin state, but not enriched in the silent state. In the caudate nucleus, the most highly affected brain region in HD, genes in the active state were associated with transcription, cell cycle, protein transport and modification, RNA splicing, histone post-translational modifications and RNA processing. Genes in the repressed state were linked with developmental processes and responses related to zinc and cadmium stimulus. We confirmed that genes within CpG-islands are enriched among HD dysregulated genes in human and mouse in HD. Epigenetic processes were associated more with genes that overlap with CpG-islands than genes that do not. Conclusion: Our results suggest that massive transcriptional dysregulation in HD is not matched by large-scale relocation of gene activity, i.e. inactive chromatin regions are altered into actively expressed chromatin regions and vice versa. We expect that changes in epigenetic chromatin state might occur at the level of single genes (e.g. promoters, gene body) and scattered genomic sites (e.g. CTCF sites, enhancer regions) instead of large-scale genomic regions.